Most vaccines licensed for use in humans are administered parenterally, which is an effective route for generating a systemic immune response. However, parenteral immunization produces predominantly IgM and IgG on mucosal surfaces, where most pathogenic or opportunistic organisms initiate infection, and is not very effective in protecting individuals from air borne or mucosal-related infectious diseases (Formal et al., Proc. Soc. Exp. Biol. Med. 125:347, 1967; Mestecky, J. J. Clin. Immunol. 7:265, 1987). Protective, antigen specific secretory IgA (sIgA) antibodies are only efficiently induced when antigen is administered to the mucosal sites (McGhee, J. R. and Mestecky, J. Infec. Dis. Clin. North. Amer. 4:315, 1990).
Several studies in the area of mucosal immunization have utilized live, attenuated viruses or bacteria as the immunogen (Treanor et al., Ann. Intern. Med. 117:625, 1992; Clements et al., Vaccine 6:269, 1988). In these studies, administration of the attenuated microbes resulted in effective protection and induced both local and systemic immunity. Intranasal administration of particulate antigens has also been described (Peter et al. Infec. and Immun. 40:1092, 1983). However, administration of soluble antigens to mucosal surfaces has been hampered by the lack of appropriate delivery vehicles or soluble adjuvants that stimulate mucosal IgA secretion.
New delivery methods, including synthetic or naturally occurring polymers, and liposome preparations, have been investigated as means for the controlled and/or targeted delivery of soluble immunogens. Abraham (Vaccine 10:461, 1992) reported that the intranasal administration of liposome-contained antigen reduced the dose of antigen required to elicit a mucosal immune response. Almeida and co-workers (J. Pharm. Pharmacol. 45:198, 1993) reported similar findings using poly (L-lactic acid) microspheres. Several other types of microspheres have also been investigated for use as vaccine antigen carriers. In one study, uptake by gut-associated lymphoid tissue (GALT), a necessary first step in generating a protective immune response, was dependent upon the type and diameter of the microparticle (Eldridge et al., J. Controlled Release 11:205, 1990). Other hydrogels have also been used for oral vaccination of animals (Bowerstock et al., Pro. Intern. Symp. Control. Rel. Bioact. Mater. 21:79. 1994).
Alginate is a pH-sensitive, biodegradable material that forms a gel matrix in the presence of divalent cations, and has been used in microencapsulation technology for entrapment of antibodies, subcellular organelles, cells, bacteria, nucleic acids and proteins (Tai et al., FASEB. 7:1061, 1993; Smidsrod, O. and Skjak-Braek, G. TIBTECH 8:71, 1990; Smith, T. J., BioPharm. 7:54, 1994; Duff, R. G., TIBTECH 3:167, 1985; Downs, et al., J. Cell Physiol., 152:422, 1992; Puolakkainen et al., Gastroenterology 107:1319, 1994; Soon-Shiong et al., Lancet 343:950, 1994), and for other pharmaceutical agents (Stockwell, et al., J. Controlled Release, 3:167, 1986; Segi, et al., Chem. Pharm. Bull., 37:3092, 1989; Bahkoo, et al., Pro. Int. Symp. Controlled Release Bio. Mater. 18:441, 1991).
Recent efforts in vaccine design have focused on improved vaccine delivery systems (Langer, R. Science, 249: 1527, 1990). A vaccine delivery system that can provide both priming and boosting administrations in a single dose would be very beneficial. Additionally, a system that could protect proteins and other agents from hostile environments, i.e., the low pH and battery of proteolytic or digestive enzymes present in the stomach, would facilitate development of effective vaccines. There is also a need in the art for vaccine delivery systems that utilize only small amounts of antigen, to allow simultaneous administration of more than one immunogen. Such a delivery system for soluble vaccine antigens would also allow self-administration, and would enhance the ability of health professionals to control or eliminate infectious diseases.